Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two of the major cell types in bone marrow stroma, macrophages and fibroblasts, have been shown to be important regulators of both myelopoiesis and lymphopoiesis. The enzymology relating to cell-specific metabolism of phenolic metabolites of benzene in isolated mouse bone marrow stromal cells was examined. Fibroblastoid stromal cells had elevated glutathione-S-transferase (4.5-fold) and DT-diaphorase (4-fold) activity relative to macrophages, whereas macrophages demonstrated increased UDP-glucuronosyltransferase (UDP-GT, 7.5-fold) and peroxidase activity relative to stromal fibroblasts. UDP-GT and glutathione-S-transferase activities in macrophages and fibroblasts, respectively, were significantly greater than those in unpurified white marrow. Aryl sulfotransferase activity could not be detected in either bone marrow-derived macrophages or fibroblasts, and there were no significant differences in GSH content between the two cell types. Because UDP-GT activity is high in macrophages, these data suggest that DT-diaphorase levels would be rate limiting in the detoxification of benzene-derived quinones in bone marrow macrophages. The peroxidase responsible for bioactivation of benzene-derived phenolic metabolites in bone marrow macrophages is unknown but has been suggested to be prostaglandin H synthase (PGS). Hydrogen peroxide, but not arachidonic acid, supported metabolism of hydroquinone to reactive species in bone marrow-derived macrophage lysates. These data do not support a major role for PGS in peroxidase-mediated bioactivation of hydroquinone in bone marrow-derived macrophages, although PGS mRNA could be detected in these cells. Similarly, hydrogen peroxide, but not arachidonic acid, supported metabolism of hydroquinone in a human bone marrow homogenate. Peroxidase-mediated interactions between phenolic metabolites of benzene occurred in bone marrow-derived macrophages. Bioactivation of hydroquinone to species that would bind to acid-insoluble cellular macromolecules was increased by phenol and was markedly stimulated by catechol. Bioactivation of catechol was also stimulated by phenol but was inhibited by hydroquinone. These data define the enzymology and the cell-specific metabolism of benzene metabolites in bone marrow stroma and demonstrate that interactions between phenolic metabolites may contribute to the toxicity of benzene in this critical bone marrow compartment.
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PMID:Cell-specific metabolism in mouse bone marrow stroma: studies of activation and detoxification of benzene metabolites. 148 Jan 34

The formation of benzo[a]pyrene (BP)-3,6 quinol glucuronides in liver microsomes in the presence of UDP-glucuronic acid and NAD(P)H appears to occur by a sequence of three reactions: BP-3,6-quinone----BP-3,6 hydroquinone----BP-3,6-quinol monoglucuronide----BP-3,6-quinol diglucuronide. This conclusion is based on the following results. Incubations with [14C]BP-3,6-quinone or UDP-[14C]glucuronic acid and analysis of the samples by TLC established the existence and identity of the two BP-3,6-quinol glucuronides which exhibit different fluorescence spectra. The nature of the monoglucuronide, i.e., a quinol and not a semiquinone glucuronide, was suggested by the finding that the rate of diglucuronide formation was the same with or without NAD(P)H provided that a sufficient amount of monoglucuronide had been formed prior to oxidation of the nucleotides. Furthermore, BP-3,6-quinol monoglucuronides can serve as substrates in the formation of diglucuronides. The ratio between the decrease in monoglucuronides and the formation of diglucuronides was found to be close to 1, suggesting that the conversion of the monoglucuronide of BP-3,6-quinol to the diglucuronide is also catalyzed by UDP-glucuronosyltransferase. However, great differences in the pattern of induction of mono- and diglucuronide formation indicate that two different UDP-glucuronosyltransferases are involved. The yield of BP-3,6-quinol glucuronides with NADH relative to NADPH and the increase in glucuronide formation observed in the presence of cytosolic DT-diaphorase (NAD(P)H-quinone oxidoreductase) are discussed with regards as to whether DT-diaphorase plays an important role as a BP-3,6-quinone reductase in the formation of BP-3,6-quinol glucuronides compared to other NAD(P)H-oxidizing flavoproteins.
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PMID:Formation of benzo[a]pyrene-3,6-quinol mono- and diglucuronides in rat liver microsomes. 401 1

A number of genes under the control of the arylhydrocarbon (Ah) receptor were tested for the effects of glucocorticoids on their expression in cultured primary rat hepatocytes. Treatment of cultured hepatocytes with 1.0 microM dexamethasone potentiated the induction (2- to 3-fold) of cytochrome P4501A1, glutathione S-transferase Ya subunit (GSTYa), and UDP-glucuronosyltransferase gene expression by polycyclic aromatic hydrocarbons (PAH), whereas the glucocorticoid agonist suppressed PAH induction of NAD(P)H:quinone oxidoreductase (QOR) subunit and aldehyde dehydrogenase 3C gene expression by 60-80%. These results were seen at the level of enzyme activity for induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin and at the level of enzyme activity, protein, and specific mRNA for induction by 1,2-benzanthracene. Two of these rat genes, GSTYa and QOR are also induced by electrophilic agents, such as t-butylhydroquinone. In the presence of t-butylhydroquinone, dexamethasone caused a similar level of potentiation of GSTYa subunit expression and suppression of QOR subunit expression as was seen with the PAH, 1,2-benzanthracene. Studies using the glucocorticoid receptor antagonist, RU38486, demonstrated that the modulation of PAH induction by glucocorticoids of cytochrome P4501A1 and QOR activity is apparently dependent on action of the glucocorticoid receptor. These results suggest that the positive and negative changes observed are the result of specific alterations in the rates of transcription of these genes because of the action of the glucocorticoid receptor, thereby affecting regulation of GSTYa and QOR by both Ah receptor-dependent and independent mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the Ah gene battery via Ah receptor-dependent and independent processes in cultured adult rat hepatocytes. 758 46

The glucosinolate hydrolysis product 1-isothiocyanato-3-(methylsulfinyl)-propane (IMSP), also known as iberin, is consumed in the average human (US) diet at approximately 1 mumol/kg/day. The chemoprotective effects observed with the consumption of cruciferous vegetables may be due to the presence of specific glucosinolate hydrolysis products either within the crucifers, or formed after ingestion of the crucifers. The mechanism of chemoprotection may be through selective induction of components of Phase II xenobiotic metabolizing enzymes. The influence of repeated administration of low concentrations of IMSP by gavage on components of Phase I and Phase II xenobiotic metabolizing systems was examined in the liver and small intestine of male Fischer 344 rats. Doses of 1, 10 and 100 mumol IMSP/kg, administered by gavage for 7 days, did not alter weight gain, or hepatic and renal weights, relative to body weight, and did not cause any histological lesions. Intestinal glutathione S-transferase (GST) activity and NAD(P)H:quinone reductase (QR) activities were significantly elevated to 3.1 and 8.1 times control values, respectively, at the 100 mumol/kg dose only. The administration of IMSP at 1, 10 or 100 mumol/kg had no significant effect on hepatic Phase I enzymes activities (cytochrome P-450 concentrations, ethoxycoumarin O-deethylase [ECD] and aminopyrine N-demethylase [AND] activities) or Phase II enzyme activities (GST, QR and UDP-glucuronosyltransferase [UDP-GT] activities towards 1-naphthol or 4-hydroxybiphenyl), at any of the doses tested and no effect on intestinal enzyme activities at doses below 100 mumol IMSP/kg. It is concluded that IMSP does not have a significant influence on induction of the Phase I or Phase II xenobiotic metabolizing enzymes in rats when tested at doses approximating those found in the human diet.
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PMID:Effects of 1-isothiocyanato-3-(methylsulfinyl)-propane on xenobiotic metabolizing enzymes in rats. 822 30

4-Methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz) and several other dithiolethiones protect against the acute toxicities of many xenobiotics and are effective inhibitors of experimental carcinogenesis. These protective effects are mediated, in part, through elevation of glutathione S-transferase, NAD(P)H: quinone reductase and UDP-glucuronosyltransferase activities in the liver and other target tissues. The induction of these phase 2 enzymes by oltiprax results from enhanced transcription. In the present study, the molecular mechanisms of these inductions were analyzed utilizing a construct containing a 41 bp enhancer element derived from the 5'-upstream region of the mouse liver glutathione S-transferase Ya subunit gene ligated to the 5' end of the isolated promoter region of this gene, and inserted into a plasmid containing a human growth hormone reporter gene. When this construct was transfected into murine Hepa 1c1c7 hepatoma cells, the concentrations of 25 dithiolethiones and related analogs required to double growth hormone production were determined and spanned a range nearly three orders of magnitude. Concentrations of dithiolethiones required to double the specific activity of NAD(P)H: quinone reductase were also determined in Hepa 1c1c7 cells. There was a positive correlation (r = 0.78) between the potencies of the 21 active compounds as inducers of both NAD(P)H: quinone reductase activity and growth hormone production. Moreover, no dithiolethiones were inactive in only one system. It is probable, therefore, that the induction of NAD(P)H: quinone reductase and other phase 2 enzymes by oltipraz and other dithiolethiones is mediated entirely through the 41 bp enhancer element.
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PMID:Regulation of phase 2 enzyme induction by oltipraz and other dithiolethiones. 831 5

The regulation of hepatic P450s has been the focus of numerous studies because of the importance of these proteins in endocrinology, oncology, and toxicology, as well as drug development. Considerable evidence exists demonstrating that many hepatic P450s are regulated by developmental, sex, or hormonal factors in addition to receptors that interact with foreign chemicals. The focus of work in our laboratory has been on the effects of steroid hormones, especially glucocorticoids, on expression of genes regulated by the Ah receptor. We have shown that most rat hepatic genes of the Ah receptor gene battery are regulated by glucocorticoids. We have used glucocorticoid-deficient animal models to demonstrate that these steroids do modulate the expression (basal and inducible) of these genes in vivo. Using cultured rat hepatocytes, we have demonstrated that polycyclic aromatic hydrocarbon (PAH) induction of cytochrome P4501A1, glutathione S-transferase Ya1, and UDP-glucuronosyltransferase 1*6 are apparently potentiated two- to fourfold upon inclusion of glucocorticoids in the media to activate the glucocorticoid receptor and further, that the receptor antagonist RU 38486 reverses these phenomenon. NAD(P)H:quinone oxidoreductase and aldehyde dehydrogenase 3 gene expression were repressed 70-80% by glucocorticoids in cultured hepatocytes through a glucocorticoid receptor-mediated process as well. The effect of glucocorticoid concentration on PAH induction of glutathione S-transferase Ya1 subunit for glucocorticoids was biphasic, but at physiological concentrations gene expression was repressed to approximately 20-40% of control. At supraphysiological concentrations, glucocorticoids alone induced expression two- to threefold and potentiated the PAH-inducible expression of the Ya1 subunit gene. Subsequent work in our laboratory has focused on defining the molecular basis of this hormonal regulation, specifically elucidating responsive elements responsible for the action of the glucocorticoid receptor and the mechanisms by which some of these genes are positively regulated and others are negatively regulated.
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PMID:Hormonal regulation of hepatic enzymes involved in foreign compound metabolism. 890 7

The induction of hepatic and intestinal cytochrome P450, NAD(P)H:quinone oxidoreductase (QOR), glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UGT) activities by intragastric administration of 1,7-phenanthroline, 2,2'-dipyridyl, and oltipraz has been investigated in rats. In the liver, all three compounds induced phase II drug-metabolizing enzymes without inducing overall cytochrome P450 concentrations and, in a direct comparison, all agents induced the enzymes to a greater extent than did the same dose of tert-butyl-4-hydroxyanisole. With a 75 mg/kg daily, 3-day regimen, UGT, GST, and QOR activities were induced by all compounds. The changes in hepatic GST, QOR, and UGT activities induced by N-heterocyclic compounds were accompanied by increases in the amounts of mRNA for GST Ya (2-2.4-fold), QOR (1.6-2.8-fold), and the UGTs UGT2B1 (4-6-fold) and UGT1A6 (4-10-fold). Changes in the amounts of UGT2B1 mRNA and UGT1A6 mRNA were highly correlated (r = 0. 9), but there was no correlation between changes in either UGT2B1 or UGT1A6 mRNA and GST Ya mRNA. No significant mRNA changes were elicited by tert-butyl-4-hydroxyanisole. Neither GST nor UGT activities were induced in the small intestinal mucosa by any agent. QOR activity was slightly induced by oltipraz. The data suggest that requirements for induction of phase II enzymes in the intestine are markedly different from requirements in the liver.
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PMID:Phase II-selective induction of hepatic drug-metabolizing enzymes by oltipraz -5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione-, 1,7-phenanthroline, and 2,2'-dipyridyl in rats is not accompanied by induction of intestinal enzymes. 945 93

Novel thiazolidine prodrugs were prepared by the condensation of L-cysteine with aldose disaccharides. Using a disaccharide in prodrug construction allows for a terminal cyclic sugar moiety to be present on the prodrug, which may allow the delivery of the agent to specific receptors, such as the asialoglycoprotein receptor (ASGPR) of hepatocytes, that require specific structural motifs for recognition. Three L-cysteine prodrugs were synthesized with a pendant cyclic galactose moiety; two related glucose-bearing prodrugs were synthesized for comparison. The prodrugs were designed to release L-cysteine, which is then available to support glutathione (GSH) biosynthesis and provide cytoprotection against a variety of toxic insults. Protection studies in Swiss-Webster mice used acetaminophen (575 mg/kg), a well-documented hepatotoxin which depletes GSH at overdose. Three prodrugs performed exceptionally well against acetaminophen-induced hepatotoxicity, as measured by increased survival and improved histological profiles of liver tissue after 48 h. In further experimentation, two of the disaccharide-based prodrugs, prepared from alpha- and beta-lactose, were compared with the monosaccharide-based compound prepared from ribose. Co-administration of the selected prodrugs with a 400 mg/kg dose of acetaminophen to Swiss-Webster mice prevented the short-term depletion in hepatic GSH and also reduced hepatotoxicity as determined by histological damage and serum levels of alanine aminotransferase. A single dose of the prodrugs alone had no effect on hepatic drug metabolizing enzymes [glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase (QOR), UDP-glucuronosyltransferase (UGT), and cytochrome P450], but, concordant with the reduction of hepatotoxicity, the latentiated forms prevented the significant elevation in QOR activity and mRNA and GST mRNA elicited by acetaminophen itself. GST activity, UGT activity and mRNA, and cytochrome P450 concentration were all unaffected by acetaminophen or the prodrugs. These studies identified novel L-cysteine prodrugs with potentially useful hepatoprotective activity. However, no structure-activity relationships were obvious. In addition, the occurrence of targeted delivery to hepatocytes remains ambiguous.
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PMID:Differential chemoprotection against acetaminophen-induced hepatotoxicity by latentiated L-cysteines. 981 87

1. Changes in the major hepatic drug-metabolizing enzymes by compounds identified as atypical inducers (multienzyme response but devoid of cytochrome P450-inducing ability) in rat were investigated in mouse. Animals were treated with 1,7-phenanthroline, 2,2'-dipyridyl, 7,8-benzoquinoline and oltipraz at 75 and 150 mg/kg daily for 3 days. 2. UDP-glucuronosyltransferase (UGT) activities showed only limited changes, UGT activity towards 4-nitrophenol and 1-naphthol was induced by the 75 mg/kg dose of 2,2'-dipyridyl and UGT activity towards morphine was induced by 150 mg/kg doses of 7,8-benzoquinoline and oltipraz. UGT activity towards oestrone was not induced by any treatment regimen and showed a decrease following treatment with the lower dose of 7,8-benzoquinoline. 3. In contrast with the limited effect on UGT activities, glutathione S-transferase and NAD(P)H:quinone oxidoreductase activities were significantly elevated by most compounds. Glutathione S-transferase activity was significantly elevated by the 150 mg/kg dose of 1,7-phenanthroline (73%), 2,2'-dipyridyl (52%) and oltipraz (75%), and also the lower dose of 1,7-phenanthroline (47%). NAD(P)H:quinone oxidoreductase activity was significantly elevated by the higher dose of all N-heterocycles (155-323%) as well as the lower dose of 1,7-phenanthroline (180%). 4. In contrast with the effect previously seen in rat, 7,8-benzoquinoline significantly elevated mouse cytochrome P450 concentration but not 7-ethoxyresorufin O-dealkylase activity. As in rat, no N-heterocycle-containing compound significantly elevated pentoxyresorufin O-dealkylase activity. 5. Overall, mouse show a more limited response in the range of drug-metabolizing enzymes induced by N-heterocycles compared with rat, but as in rat, cytochrome P450 was largely unaffected.
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PMID:Drug-metabolizing enzyme induction by 2,2'-dipyridyl, 1,7-phenanthroline, 7,8-benzoquinoline and oltipraz in mouse. 984 42

1. The herbicides butachlor (2-chloro-2',6',diethyl-N-[buthoxymethyl] acetanilide) and pretilachlor (2-chloro-2',6'-diethyl-N-[2-propoxyethyl] acetanilide) are widely used in Asia, South America, Europe and Africa. Isoprothiolane (diisopropyl-1,3-dithiolan-2-ylidenemalonate) is used as a fungicide and an insecticide in rice paddies. We administered these agrochemicals to the male rat and examined their effects on cytochrome P450 (P450), glutathione S-transferase (GST), UDP-glucuronosyltransferase (UDPGT), and NAD(P)H-quinone oxidoreductase 1 (NQO1)-related metabolism in the liver. 2. Administration of isoprothiolane, butachlor or pretilachlor to rat induced hepatic P4502B subfamily-dependent enzyme activities (pentoxyresorufin O-depentylation and testosterone 16 beta-hydroxylation) up to 271-413% of control, which coincided with the increase in expression levels of the P4502B apoprotein. 3. Activities of GST toward 1-chloro-2,4-nitrobenzene and 3,4-dichloronitrobenzene were slightly induced (127-133% of control) in the liver of the rat treated with these pesticides. On the other hand, marked elevations of UDPGT activities toward p-nitrophenol (164-281% of control) were observed. NQO1-related metabolism (menadione reductase activity) was also induced (123-176% of control) in the liver of rat treated with these agrochemicals. 4. These results indicate that some of the agrochemicals currently in use are capable of inducing phase I and II xenobiotic-metabolizing enzyme activities in an isozyme selective manner. The induction of these activities may disrupt normal physiologic functions related to these enzymes in exposed animals.
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PMID:Effects of the agrochemicals butachlor, pretilachlor and isoprothiolane on rat liver xenobiotic-metabolizing enzymes. 987 35


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